Gram-negative bacterial infections in surgical intensive care unit patients following abdominal surgery: high mortality associated with Stenotrophomonas maltophilia infection

Background Stenotrophomonas maltophilia, a multidrug-resistant gram-negative bacteria (GNB), is an emerging nosocomial pathogen. This study assessed the clinical outcomes of GNB infections in surgical intensive care unit (SICU) patients post-abdominal surgery, focusing on the differences between S. maltophilia and other GNBs, including Pseudomonas aeruginosa. Methods A retrospective study was conducted on SICU patients at Kaohsiung Chang Gung Memorial Hospital from 2010 to 2020, who developed GNB infections following abdominal surgery. Results Of 442 patients, 237 had S. maltophilia and 205 had non-S. maltophilia GNB infections (including 81 with P. aeruginosa). The overall mortality rate was 44.5%, and S. maltophilia infection emerged as a significant contributor to the mortality rate in patients with GNB infections. S. maltophilia patients had longer mechanical ventilation and SICU stays, with a 30-day mortality rate of 35.4%, higher than the non-S. maltophilia GNB (22.9%) and P. aeruginosa (21%) groups. In-hospital mortality was also higher in the S. maltophilia group (53.2%) compared to the non-S. maltophilia GNB (34.6%) and P. aeruginosa groups (29.6%). Risk factors for acquiring S. maltophilia included a higher Sequential Organ Failure Assessment score and prior broad-spectrum antibiotics use. Older age, polymicrobial infections, and elevated bilirubin were associated with increased 30-day mortality in S. maltophilia patients. Conclusion S. maltophilia infections in post-abdominal surgery patients are linked to higher mortality than non-S. maltophilia GNB and P. aeruginosa infections, emphasizing the need for early diagnosis and treatment to improve outcomes.


Introduction
Infections are prevalent among patients in intensive care units (ICU) and significantly contribute to mortality.The study on infection prevalence in ICU found that 51% of patients were infected, with gram-negative bacteria (GNB) identified as a frequent cause [1,2].Previous studies have highlighted Pseudomonas aeruginosa as a common nosocomial pathogen in the ICU setting, which carries a high mortality rate in patients, particularly when effective antibiotic therapy is delayed [3,4].However, the emergence of Stenotrophomonas maltophilia, an opportunistic GNB pathogen prevalent on surfaces within hospital environments, has increasingly been identified as a major culprit in ICU infections [5,6].S. maltophilia, inherently resistant to several classes of antibiotics, such as cephalosporins and carbapenems, is widely recognized as a challenging organism to treat [7].Consequently, patients with S. maltophilia infections often face poor outcomes, including prolonged ICU stays and elevated mortality rates [8,9].Surgical patients, as a vulnerable population, necessitate heightened vigilance due to their augmented susceptibility to bacterial infections [10].While S. maltophilia infections have been reported in ICU and trauma patients [11,12], there is limited information available regarding the abdominal surgical population in the surgical ICU (SICU) setting, particularly in evaluating the impact of S. maltophilia infection on clinical outcomes.The objective of our study was to investigate the clinical features and outcomes of GNB infection, especially discerning the differences between S. maltophilia and non-S.maltophilia GNB, including P. aeruginosa infection, in SICU patients who underwent abdominal surgery.This information is particularly crucial in an era of advanced, complex surgical procedures and growing concerns about antimicrobial-resistant pathogens in the SICU, where timely and effective treatment may mitigate otherwise preventable morbidity and mortality in critically ill SICU patients.

Ethics approval
This study received approval from the Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital (202200091B0C601), Taiwan.Informed consent was not necessary as the data were analyzed anonymously.

Study design, setting, and participants
A retrospective study was conducted to analyze all consecutive adult patients (aged 20 years or older) who underwent abdominal surgery and were admitted to the SICU for three days or longer at Kaohsiung Chang Gung Memorial Hospital, a 2,600-bed primary care and tertiary academic medical center in Taiwan, from January 2010 to December 2020.
The exclusion criteria included patients who did not undergo abdominal surgery, those with gram-positive bacterial infections, and those without GNB infections following abdominal surgery.The inclusion criteria encompassed patients who underwent abdominal surgery and subsequently developed GNB infections.For patients who experienced multiple episodes of GNB infection during the same admission, only the initial GNB episode or the first episode of polymicrobial infection involving GNB was considered for analysis in this study.These patients were categorized into two groups: those with S. maltophilia infections and those with non-S.maltophilia GNB, including P. aeruginosa infections.

Definitions
The surgical site classification in this study comprised four distinct areas.The first category encompassed the digestive system, which included the esophagus, stomach, duodenum, small intestine, colon, appendix, and rectum.The second category encompassed surgeries on the hepatobiliary system, pancreas, and spleen.The third category involved genitourinary surgeries, including the kidneys.Finally, the fourth category was focused on surgeries involving the abdominal wall.Antipseudomonal penicillins referred to piperacillin-tazobactam, while antipseudomonal cephalosporins included ceftazidime, cefoperazone-sulbactam, and cefepime.Carbapenems encompassed ertapenem, imipenem, meropenem, and doripenem.Fluoroquinolone referred to levofloxacin and ciprofloxacin.GNB infection is defined by the identification of GNB in a specimen from the affected site, supported by laboratory, radiological, and clinical evidence indicative of infection, sepsis, or septic shock [13].Polymicrobial infection was defined as the concurrent isolation of multiple microorganisms, including GNB, from a blood specimen, along with clinical signs of infection.The in-hospital mortality refered to all-cause mortality that occurs during the hospital admission.

Antimicrobial susceptibility testing
Microbiology laboratories performed antimicrobial susceptibility tests on the isolates using disk diffusion or automated testing methods (BD Phoenix™), following the guidelines and breakpoints outlined by the Institute of Clinical Laboratory and Standards [14].Non-susceptibility was ascertained based on results obtained from in vitro antimicrobial susceptibility testing, indicating resistance, or intermediate susceptibility.The antimicrobial agents tested for S. maltophilia included trimethoprim/ sulfamethoxazole, levofloxacin, moxifloxacin, and tigecycline, following the recommendations of Institute of Clinical Laboratory and Standards [14].

Data collection
For our analysis, we collected a variety of variables including demographic information, Charlson's comorbidity index [15], Sequential Organ Failure Assessment (SOFA) Score [16], the American Society of Anesthesiologists (ASA) physical status classification [17], surgical wound classification [18], types of surgical sites, duration of the surgical procedure, and any repeat surgeries during the same ICU stay.We also recorded data on various interventions, including mechanical ventilation, total parenteral nutrition, hemodialysis, blood transfusions, and catheter placements.Medication details, such as those pertaining to chemotherapy, immunosuppressants, steroids, and antibiotics, were gathered.Additionally, relevant laboratory results, including levels of albumin, alanine aminotransferase, creatinine, hemoglobin, platelet count, and total bilirubin, were taken into consideration.Lastly, we recorded outcomes such as the duration of mechanical ventilation, length of SICU stay, and both 30-day and in-hospital mortality rates post-GNB infection for a comprehensive analysis.

Statistical analysis
Univariate and multivariate analyses were performed to evaluate the risk factors associated with all-cause mortality in patients with GNB infections included in the study.For a comprehensive understanding of GNB infection characteristics, univariate analysis was carried out to examine clinical and laboratory features, as well as outcomes, differentiating between patients with S. maltophilia and those with non-S.maltophilia GNB infections, such as P. aeruginosa.Furthermore, a comparative analysis between S. maltophilia and non-S.maltophilia GNB infections was performed to elucidate the risk factors predisposing patients to S. maltophilia infection.Kaplan-Meier curves were generated to compare 30-day survival between (a) patients with S. maltophilia infection and those with non-S.maltophilia GNB infection, and (b) patients with S. maltophilia infection and those with P. aeruginosa infection.Lastly, we conducted a comparative analysis between survivors and non-survivors to identify the independent risk factors associated with 30-day mortality after S. maltophilia infection.
Continuous variables are presented as means ± standard deviations, or median (interquartile range) while categorical variables are expressed as numbers and percentages.The Student's t-test was employed for continuous variables, and the chi-square or Fisher's exact test was utilized for categorical variables, as appropriate.Multivariate analysis was conducted utilizing a logistic regression model and a stepwise procedure to identify independent risk factors associated with the acquisition of S. maltophilia infection and 30-day mortality subsequent to S. maltophilia infection.All significance tests were two-sided, with a significance level set at P < 0.05.Statistical analyses were conducted using SAS EG version 5.1.

Results
Figure 1 presents the flowchart of the study.From a total of 1,278 patients who underwent abdominal surgery and subsequently developed bacterial infections, 442 were identified with GNB infections.Of these, 237 patients were diagnosed with S. maltophilia infection, while the remaining 205 had non-S.maltophilia GNB infections, which included 81 patients with P. aeruginosa infections.Table 1 details the characteristics of these 442 patients, categorizing them into those with S. maltophilia infections and those with non-S.maltophilia GNB infections, inclusive of P. aeruginosa infections.
When comparing patients with S. maltophilia infections to those with P. aeruginosa infections, findings were largely parallel to those observed in the comparison with non-S.maltophilia GNB infections.However, there were exceptions in certain variables.These included surgical wound classification, the occurrence of repeat surgeries, hemodialysis, blood transfusions, the use of surgical drainage catheters, the presence of polymicrobial infections, and the use of antipseudomonal cephalosporins, where no statistical significance was observed.(Table 1).

Comparative analysis of clinical outcomes among patients with S. maltophilia, non-S. maltophilia GNB, and P. aeruginosa infections (Table 4)
Patients with S. maltophilia infections exhibited significantly longer periods of mechanical ventilation and more extended stays in the SICU than those with non-S.maltophilia GNB infections (mean: 14.4 days vs. 9.7 days [P < 0.001], and mean: 19.7 days vs. 15.9 days [P = 0.018], respectively).Similarly, when compared with patients suffering from P. aeruginosa infections, the S. maltophilia group had longer mechanical ventilation (mean: 14.4 days vs. 9.4 days, P < 0.001) and SICU stays (mean: 19.7 days vs. 15.3 days, P = 0.011), respectively, following the onset of their respective GNB infections.The 30-day mortality rate post-GNB infections onset was 35.4% in the S. maltophilia group, which was significantly higher compared to 22.9% in the non-S.maltophilia GNB group (P = 0.004) and 21% in the P. aeruginosa group (P = 0.016).Moreover, the in-hospital mortality rate was significantly higher in the S. maltophilia group when compared to the non-S.maltophilia GNB (53.2% vs. 34.6%,P < 0.001) and P. aeruginosa (53.2% vs. 29.6%,P < 0.001) groups (Table 4).

Discussion
Our study is the first to delve into the clinical characteristics of S. maltophilia infections, comparing them with other non-S.maltophilia GNB and P. aeruginosa infections, and assessing their impact on clinical outcomes in SICU patients post-abdominal surgery.Our findings illuminate several critical insights.Firstly, there is a striking 44.5% mortality rate among abdominal surgical patients with GNB infection, with S. maltophilia infections occurring significantly more frequently in fatal cases than in survivors.Secondly, patients with S. maltophilia infection exhibited higher SOFA scores and were more frequently administered broad-spectrum antibiotics prior to the onset of the S. maltophilia infection.Thirdly, a lower 30-day survival rate and higher in-hospital mortality were observed in patients with S. maltophilia infection compared to those with non-S.maltophilia GNB and P. aeruginosa infections.Fourthly, old age, polymicrobial infection, and elevated total bilirubin levels were identified as independent risk factors for mortality among patients with S. maltophilia infection.These findings underscore the graver outcomes for abdominal surgery patients who develop S. maltophilia infection compared to those with other GNB infections, even when compared to the most common nosocomial pathogen, P. aeruginosa.This emphasizes the paramount importance of early diagnosis and treatment of S. maltophilia infection, as well as stringent infection control to mitigate the spread of S. maltophilia infection in an ICU setting.
Infections pose a pervasive challenge in ICUs, correlating with substantial morbidity and mortality [19,20].Within ICU settings, mortality rates linked to GNB infections exhibit considerable variability, typically fluctuating between 20% and 50%.This variation is influenced by the specific pathogen involved, the patient demographic, and the healthcare environment [1,21].Our series identified a notably high mortality rate of 44.5% among SICU patients who underwent abdominal surgery and subsequently developed a GNB infection.Not surprisingly, a high Charlson comorbidity index and SOFA score were identified as independent risk factors for mortality in these GNB patients.Furthermore, S. maltophilia infection emerged as a significant contributor to the mortality rate in patients with GNB infections.
A nationwide retrospective study in France, conducted by Guerci et al., revealed that 0.27% of 102,316 patients, admitted across 25 mixed ICUs over a three-year period, encountered hospital-acquired S. maltophilia pneumonia [22].Similarly, a prospective observational casecontrol study by Nseir et al. demonstrated that 2% of 1,885 patients in a 30-bed mixed ICU developed ICUacquired S. maltophilia colonization and/or infection [8].In contrast, our study identified S. maltophilia infection in 18.5% (237 of 1278 patients) of abdominal surgical patients complicated with bacterial infection in the SICU, with these infections representing 53.6% (237 of 442 patients) of SICU-acquired GNB infections post-abdominal surgery.The elevated incidence of S. maltophilia infection in our study may be attributed to our specific emphasis on the abdominal surgical patient population, whereas previous studies enrolled patients from mixed ICU settings, encompassing varied patient population characteristics.The pronounced incidence of S. maltophilia infection in abdominal surgery patients serves as a reminder for physicians to maintain heightened vigilance regarding S. maltophilia infections when managing abdominal surgical patients in the ICU.This is especially crucial considering the intrinsic resistance of S. maltophilia, which might delay the initiation of effective antibiotic treatment and potentially lead to avoidable mortality and morbidity.
Our study highlights a pronounced association between elevated SOFA scores and the incidence of S. maltophilia    [12].Furthermore, associations have been identified between the use of antipseudomonal cephalosporins and carbapenems and an elevated risk of S. maltophilia bacteremia [24].The inherent resistance of S. maltophilia to β-lactam antibiotics, such as cephalosporins and carbapenems, amplifies the risk of infection or colonization.However, the administration of broad-spectrum antibiotics is often indispensable in critically ill patients in the ICU, especially those contending with intricate intraabdominal infections.Our findings underscore the critical need for the rigorous implementation of antimicrobial stewardship programs.These should encompass empirical antibiotic use guided by local guidelines and epidemiology, optimal dosing strategies, regular reviews of antimicrobial therapy in alignment with clinical progress and microbiological findings, de-escalation as soon as feasible, and timely cessation of therapy where appropriate, all with the overarching aim to mitigate the ecological impact on the patient's microbiome and curtail the emergence of antimicrobial resistance.Remarkably, the 30-day mortality rate for S. maltophilia infection surpassed that of other non-S.maltophilia GNB infections, even exceeding the rate for P. aeruginosa, a notorious nosocomial pathogen.Previous research has underscored the elevated mortality rates associated with P. aeruginosa infections, particularly among immunocompromised and critically ill patients [3,25,26].P. aeruginosa bacteremia, acknowledged as a perilous nosocomial infection, frequently precipitates multi-site infections and exhibits a mortality rate oscillating between 18% and 36.4% in cases of bacteremia [27][28][29].Consistent with these findings, our study identified a 30-day mortality rate of 21% among abdominal surgery patients with P. aeruginosa infection.Conversely, the 30-day mortality rate for S. maltophilia infection was a staggering 35.4%, with an overarching in-hospital mortality of 53.2%.Interestingly, the rate of polymicrobial infections involving both S. maltophilia and P. aeruginosa showed no significant difference, potentially impacting mortality analysis.Patients with S. maltophilia infections exhibited higher SOFA scores, required longer mechanical ventilation, and underwent more prolonged antibiotic therapy than those with P. aeruginosa, suggesting more severe   clinical conditions and potentially increased mortality risk.The exact cause of the higher mortality in S. maltophilia patients-whether directly due to the S. maltophilia infection or underlying severe illnesses-remains unclear [30].However, our study emphasizes that beyond the known risks of P. aeruginosa, there is a critical need for surgeons and intensivists to be vigilant and proactive in detecting S. maltophilia infections to improve patient outcomes.Tunger et al. conducted a retrospective study on 35 episodes of S. maltophilia bacteremia in a tertiary academic center, pinpointing older age and renal insufficiency as mortality risk factors [31].This aligns with a systematic review by Paez et al. in 2008, which highlighted organ dysfunction as an independent mortality risk factor post S. maltophilia infection [32].Our findings resonate with these studies, emphasizing older age as a mortality predictor in S. maltophilia infection.Furthermore, we identified polymicrobial infection and elevated total bilirubin levels as significant independent predictors of 30-day mortality post S. maltophilia infection in ICU abdominal surgery patients.Notably, various studies have documented elevated mortality rates, ranging from 36 to 63%, in patients with polymicrobial bacteremia.These rates are influenced by patient comorbidities, diverse infection sources, and distinct causative pathogens [33][34][35].Previous literature has reported a high rate of polymicrobial infections in S. maltophilia bacteremia [32], consistent with our observation that 69% of non-survivors developed polymicrobial infections post S. maltophilia infection.While the administration of inappropriate antimicrobial therapy did not significantly differ between survivors and non-survivors, the emergence of polymicrobial infections suggests a more intricate disease trajectory.Surgical-induced mucosal disruption might facilitate bacterial breakthrough infections.Conversely, elevated total bilirubin levels may signify not only hepatic dysfunction but also potential mechanical biliary tract obstruction and the progression of sepsis [36].A previous study underscored that an elevation in serum bilirubin levels within the initial 72 h of admission is correlated with an augmented mortality risk in patients experiencing severe sepsis and septic shock [37].Our findings accentuate the imperative of enhanced clinical vigilance in the management of GNB infections, especially those attributed to S. maltophilia.
Our study presents several limitations.Firstly, its retrospective nature inherently imposes constraints due to missing data on indicators of inflammation such as C-reactive protein and procalcitonin.Secondly, the inclusion of patients from a single institution may limit the generalizability of our findings to broader contexts.Thirdly, the absence of data on physicians' clinical judgment concerning antimicrobial therapy might have restricted the depth of our analysis.Fourth, differences in the site of infection could potentially influence the outcomes of patients with S. maltophilia infection.

Conclusion
In summary, GNB infection, particularly involving S. maltophilia, results in a high mortality rate among SICU patients who have undergone abdominal surgery.Our findings provide clinicians with a comprehensive understanding of the clinical features and risks of GNB infections, urging healthcare professionals to promptly identify high-risk patients.Given the considerable mortality rate attributed to S. maltophilia infection, initiating early, targeted treatment strategies are vital to enhancing patient outcomes.

Fig. 2
Fig. 2 Kaplan-Meier curve comparing 30-day survival between (a) patients with Stenotrophomonas maltophilia infection and those with non-S.maltophilia gram-negative bacterial infection, and (b) patients with S. maltophilia infection and those with Pseudomonas aeruginosa infection source from ED, n (%)

Table 1 Patient characteristics Characteristics of patients with S. maltophilia infection (Table 1 )
Among the 237 patients (mean age, 68.3 years) diagnosed with S. maltophilia infection, 59 patients (24.9%) 4%) died within 30 days following the onset of S. maltophilia infection.In total, 126 out of the 237 patients died, yielding an in-hospital mortality rate of 53.2%.

Table 3
The isolates of non-Stenotrophomonas maltophilia gram-negative bacteria

Table 4
Comparing the outcomes of patients with Stenotrophomonas maltophilia infection to those with infections caused by non-S.maltophilia gram-negative bacteria and Pseudomonas aeruginosa GNB, gram-negative bacteria; ICU, intensive care unit; SD, standard deviation a Comparison between S. maltophilia and non-S.maltophiliaGNB.b Comparision between S. maltophilia and P. aeruginosa

Table 5
Comparing survivors and non-survivors within 30 days following Stenotrophomonas maltophilia infection infection.This correlation can be attributed to the frequent use of broad-spectrum antibiotics in these patients prior to the onset of S. maltophilia infection.Previous research has illuminated the role of broad-spectrum anti- , Alanine transaminase; ASA, American Society of Anesthesiologists; BMI, body mass index; CI, confidential interval; ED, emergency department; IQR, interquartile range; SD, standard deviation; SOFA, Sequential Organ Failure Assessment ALT